A new driver of premature ageing in chronic kidney disease

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The three Greek Fates, Clotho, Lachesis and Atropos, who spin, meaure and cut the thread of life respectively.

Chronic kidney disease (CKD) is a general condition characterised by a varying degree of kidney impairment. One in 10 European adults suffers from CKD, which has no cure and progressively worsens over time if adequate lifestyle changes are not made and treatments not given. This can lead to end-stage disease and kidney failure, requiring dialysis and an eventual transplant.

The most concerning aspects of CKD are premature aging and mortality, mainly from cardiovascular causes. This was believed to be a result of toxin accumulation due to underperforming kidneys, however, toxins only begin to build-up during end-stage disease whereas aging is accelerated from the early-stages. The cause remained elusive until the discovery of Klotho, a protein named the ancient Greek Fate who spins the thread of life, existing primarily in the kidneys in both transmembrane and soluble forms. Reduced production of Klotho is associated with degenerative processes such as arteriosclerosis, osteoporosis and skin atrophy. It is produced by the kidneys and quickly becomes deficient in the early stages of CKD when renal function is still relatively normal and toxin accumulation hasn’t begun.

A key question remains unanswered: what drives this reduction in Klotho in early CKD? In a new study from Universidad Autónoma de Madrid published in Nephrology Dialysis Transplantation, the authors hypothesised that the reduction in Klotho is linked to the presence of albumin in urine, a hallmark of early-stage disease. Through the investigation of cultured kidney tubular cells, one of the main sources of Klotho, they found that the level of albumin in urine is directly proportional to interstitial inflammation and reduced Klotho mRNA expression. These results were supported by experimental animal models and in patients with albuminuria but normal functioning kidneys.

"This early albuminuria-driven decrease in Klotho expression may contribute to the higher risk of premature death and CKD progression in the early stages of human CKD (stage 1 or 2, that is, normal renal function). In this regard, testing for albuminuria is as important as testing for glomerular filtration to assess CKD", said Professor Alberto Ortiz, senior author of the paper.

These findings remind us of the need for CKD patients, even at the earlier stages, to avoid the intake of large amounts of phosphate, especially highly bio-available phosphate, as found in food additives"

Professor Ortiz

The short- and long-term clinical consequences of this study could be wide-reaching. It is believed that some of Klotho’s anti-aging properties come from its relationship with phosphate retention. In the arteries, decreased Klotho leads to an increased rate of cellular differentiation of vascular smooth muscle to osteoblast-like cells. The osteoblasts take up calcium, inducing vascular calcification and eventual cardiovascular disease.

Several animal studies have shown that klotho deficient mice can be successfully rescued from premature aging by the resolution of hyperphosphataemia through dietary and genetic intervention. "In the short-term, these findings remind us of the need for CKD patients, even at the earlier stages, to avoid the intake of large amounts of phosphate, especially highly bio-available phosphate, as found in food additives. Therefore, CKD patients should favour natural foods over processed foods", explains Professor Ortiz. "With this simple dietetic measure they can maintain healthy vessels. In the long term, the involvement of epigenetic mechanisms may provide additional therapeutic tools to preserve Klotho production when currently available anti-proteinuric therapy fails".

Over the past 4 years, researchers have investigated the molecular, cellular and genetic differences between human and mouse kidneys to characterise the molecular and cellular development that occurs in human kidneys in utero.

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